The long term goal of the project is to broaden our understanding of neurological diseases due to autoimmune mechanisms and to find ways to treat such diseases. The objective of this grant is to investigate whether autoimmunity may be involved in the pathogenesis of stiff-man syndrome. Stiff-man syndrome is a rare, highly incapacitating, human diseases of the central nervous system characterized by progressive rigidity of the body musculature associated with painful spasms. The rigidity is thought to result from an impairment of suprasegmental and spinal inhibitory systems that operate through GABA. The pathogenesis of stiff-man syndrome is unknown. Recent studies have demonstrated the presence of signs of central nervous system autoimmunity and, more specifically, of autoantibodies directed against GABA-ergic nerve terminals, in a high percentage of patients affected by stiff-man syndrome. They have also suggested that glutamic acid-decarboxylase (GAD), the enzyme involved in the synthesis of GABA, may be a primary autoantigen in the disease. These results have raised the possibility that autoimmunity may be the cause of the neurological symptoms. A series of studies aimed at further testing this hypothesis are planned. It is proposed to further characterize the specificity of the autoantibodies that are found in the serum and cerebrospinal fluid of stiff-man syndrome patients and to determine whether GAD is always the primary antigen involved; to characterize other possible autoantigens by biochemical and recombinant DNA techniques; to determine if, and how, these autoantigens are directly involved in the pathogenesis of the disease; to reproduce the diseases in laboratory animals by injecting the relevant antigens. These studies may lead to new effective ways to treat stiff-man syndrome. In addition, if the working hypothesis of the project turns out to be correct, stiff-man syndrome may represent an important model disease to further elucidate the pathogenetic mechanisms involved in central nervous system autoimmunity and in autoimmunity in general.